Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment.
In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D. J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at www.accessdata.fda.gov).
In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme's activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.
A potentially attractive strategy for improving a drug's metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.
Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, M I et al, J Pharm Sci, 1975, 64:367-91; Foster, A B, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner, D J et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, M B et al, Curr Opin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p. 35 and Fisher at p. 101).
The effects of deuterium modification on a drug's metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.
This invention relates to novel derivatives of curcumin and dimethylcurcumin and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering curcumin or dimethylcurcumin.
Curcuminoids such as dimethylcurcumin are capable of acting as androgen receptor antagonists. Such compounds may be useful for the treatment of androgen-related afflictions including baldness, hirsutism, behavioral disorders, acne, alopecia, skin lesions, Kennedy's disease or spinobulbar muscular atrophy and spermatogenesis where inhibition of spermatogenesis is desired. Additionally, the compounds may be useful for treatment of psoriasis, Alzheimer's disease, mild cognitive impairment, asthma, type 2 diabetes, optic neuropathy, rheumatoid arthritis, osteoarthritis, major depressive disorder, kidney allografts, oral lichen planus, irritable bowel syndrome (IBS), ulcerative colitis, Crohn's disease, chemoradiation side effects including but not limited to radiation induced dermatitis and chemotherapy induced mucositis and cancer including, but not limited to, multiple myeloma, pancreatic cancer, myleodysplastic syndromes, colon cancer, colorectal cancer, skin cancer, small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, breast cancer, endometrial cancer, ovarian cancer, central nervous system cancer, liver cancer, prostate cancer, familial adenomatous polyposis (FAP), uterine cervical dysplasia, cutaneous T-cell lymphoma, head and neck cancer and osteosarcoma.
Dimethylcurcumin is currently undergoing clinical trial evaluation for use in topical treatment of acne and alopecia. Preclinical studies are also underway for the treatment of skin lesions and Kennedy's disease or spinobulbar muscular atrophy. Curcumin is currently undergoing clinical trial evaluation for use in treatment of asthma, type 2 diabetes, Alzheimer's disease, mild cognitive impairment, optic neuropathy, rheumatoid arthritis, osteoarthritis, major depressive disorder, kidney allografts, psoriasis, oral lichen planus, multiple myeloma, myelodysplastic syndrome, colorectal cancer, familial adenomatous polyposis (FAP), uterine cervical dysplasia, cutaneous T-cell lymphoma, head and neck cancer, pancreatic cancer, osteosarcoma, irritable bowel syndrome (IBS), ulcerative colitis, Crohn's disease, chemoradiation side effects including but not limited to radiation induced dermatitis and chemotherapy induced mucositis.
Despite the beneficial activities of dimethylcurcumin, there is a continuing need for compositions or derivatives thereof that provide the beneficial effects of dimethylcurcumin, but reduce or avoid the adverse side effects.